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Home , Corpus hemorrhagicum, Ferguson reflex, Follicular fluid, Mesometrium, Reproductive biology, Theca externa

ANSC 630: REPRODUCTIVE BIOLOGY 1

INSTRUCTOR: FULLER W. BAZER, PH.D.

OFFICE: 442D KLEBERG CENTER

EMAIL: [email protected]

OFFICE PHONE: 979-862-2659 ANSC 630: INFORMATION CARD • NAME • MAJOR • ADVISOR • RESEARCH INTERESTS • PREVIOUS COURSES: – Reproductive Biology – Biochemistry – Physiology – Histology – OVERVIEW OF FUNCTIONAL REPRODUCTIVE ANATOMY: THE MAJOR COMPONENTS

PARS NERVOSA PARS DISTALIS Hypothalamic Neurons Hypothalamic Neurons Melanocyte Supraoptic Stimulating Releasing Paraventricular Factor

Axons Nerve Tracts

POSTERIOR PITUITARY INTERMEDIATE LOBE OF (PARS NERVOSA) - Neurophysin PITUITARY Vasopressin-Neurophysin Melanocyte Stimulating Hormone (MSH)

Hypothalamic Divisions

Yen 2004; Reprod Endocrinol 3-73 Hormone Profile of the Estrous Cycle in the Ewe

100 30 30

50 15 15

GnRH (pg/ml) GnRH GnRH (pg/ml) GnRH 0 0 (pg/ml) GnRH 0 4 h 4 h 4 h

PGF2α

Concentration

0 5 10 16 0 Days

LH FSH Estradiol Development of the Hypophysis

Dubois 1993 Reprod Mamm Man 17-50 Neurons • Cell body (soma; perikaryon) – Synthesis of neuropeptides • Cellular processes • Dendrites • Axon - Transport • Terminals – Storage and Secretion Yen 2004 Reprod Endocrinol 3-73

• Peptide neurotransmitter synthesis • Transcription – Gene transcribes mRNA • Translation – mRNA translated for protein synthesis • Maturation – post-translational processing • Storage in vesicles - Hormone secreted from vesicles • Mid-central base of brain – Optic chiasma – 3rd ventricle – Mammillary body • Nuclei – Clusters of neurons • Different functions & stimuli for hormone secretion – Secrete peptide • Control pituitary activity • Vascular connections • Neural connections

• Vascular connection to – Hypothalamo-hypophyseal portal system • Axons to capillaries in pituitary stalk where GnRH and Dopamine is released

• Blood to AP – Superior Hypophyseal Artery (SHA) – Primary Portal Plexus (PPP) – Secondary Portal Plexus (SPP) – GnRH – releases LH and FSH – Dopamine – Prolactin Inhibiting Factor

Hypothalamohypophyseal Portal Vasculature

• Hypophysiotropic peptidergic or aminergic neurons terminate adjacent to the primary capillaries of the infundibulum (3, 5) or adjacent to the capillaries of the short portal vessels (2)

• Neurohypophyseal neurons project to the neurohypophysis and secrete neurohormones into the sinusoids of the neurohypophysis Hypothalamohypophyseal Portal Vasculature

• Blood supply – Internal carotid artery • Superior hypophyseal artery (rostral) • Inferior hypophyseal artery (caudal) – infundibulum and neurophypophysis • Anterior hypophyseal artery (trabecular artery; mediorostral) Hypothalamic Regulation of Anterior Pituitary Hormones • Gonadotropin Releasing Hormone – GnRH • Corticotrophin Releasing Hormone – CRH • Thyrotrophin Releasing Hormone – TRH • Growth Hormone Releasing Hormone – GHRH • Growth Hormone Inhibiting Factor- Sommatostatin • Prolactin Inhibiting Factor – Dopamine • Prolactin Stimulating Factors - oxytocin, Preoptic Area and Hypothalamus

INPUTS Light:Dark Ratio Smell Nutritional Status HYPOTHALAMUS Sight Stress Neurotransmitters Neurotransmitters/Neurohormones • Amino acid derivatives • Cathecholamines: dopamine, norepinephrine, epinephrine • Derived from phenylalanine and tyrosine

Lovejoy 2005; Neuroendocrinology 119-148 Hypothalamus GnRH, PIF,GHRH, CRH, TRH

Hyphothalamo-Hypophyseal Portal System ANTERIOR GONADOTROPHS Follicle Stimulating Hormone (FSH) (LH) LACTOTROPHS Prolactin (PRL) SOMATOTROPHS Growth Hormone (GH) THYROTROPHS Stimulating Hormone (TSH) CORTICOTROPHS Adrenocorticotrophin Stimulating Hormone (ACTH) Pituitary

• Anterior Lobe • Posterior Lobe • Adenohypophysis • Neurohypophysis • Pars distalis • Pars nervosa – Endoectoderm origin – Neuroectoderm origin – Produces – Stores and releases • FSH • Vassopressin • LH • Oxytocin • PRL • GH • Intermediate Lobe • ACTH • • TSH – Neuroectoderm origin

Hypothalamic Neurons Hypothalamic Neurons Melanocyte Supraoptic Stimulating Hormone Releasing Paraventricular Factor

Axons Nerve Tracts

POSTERIOR PITUITARY INTERMEDIATE LOBE OF (PARS NERVOSA) Oxytocin - Neurophysin PITUITARY Vasopressin-Neurophysin Melanocyte Stimulating Hormone (MSH)

• Neural Supply to PP – • Vassopressin-Neurophysin I – Paraventricular nucleus • Oxytocin-Neurophysin I – Neurophysins  Chaperone peptide forms complex with oxytocin and neurophysin  Hormone-Neurophysin Complex Transported via axons to Nerve Terminals in the Posterior Pituitary Gland – Neural stalk  Axons release Oxytocin + Neurophysin I or Vasopressin + Neurophysin I into capillaries draining Posterior Pituitary

Neuro-Endocrine Reflex (epiphysis)

• Photoreceptor in amphibians

• in – Influenced by light and season – Secretes melatonin • Melatonin Influences GnRH secretion – Long-day breeders - Horse

– Short -day breeders - Sheep Female Reproductive Anatomy

• • • • • • Vestibule • •

Female Reproductive Anatomy

• Ovaries • Oviducts • Uterus • Cervix • Vagina • Vestibule • Vulva • Clitoris Ovarian Architecture

• Cortex –outer zone – Covered by germinal epithelium • Medulla – inner zone – Loose connective tissue – Stroma continuous with stroma of at hilus most species equine

Follicular Fluid

Theca cells

Zona Pellucida With Nucleus

Corona Radiata Cumulus Oopherus (cumulus granulosa cells) Mural Granulosa Cells Basement Membrane

GDF, growth differentiation factor 9

BMP, bone morphogenic protein

AA – amino acid

SCF, stem cell factor

LH-R, LHCGR, luteinizing hormone receptor • Functions – – ovum, ova – Steroidogenesis – , progesterone • Round, almond- or bean-shaped – Depends on species • Paired – Most species, completely surrounded by a thin membrane, the infundibulum, which is a part of the . • Suspended – caudal to kidneys in sublumbar region by the mesovarium (part of the broad supporting the entire ) Ovarian Histology

• Germinal epithelium – simple squamous or low cuboidal • covers free surface of ovary • basement membrane absent • Tunica albuginea – dense layer of connective tissue beneath the germinal epithelium Ovarian Histology • Primordial follicles – immediately beneath the tunica albuginea – lacks a membrane – separated from adjacent interstitial tissue by a single layer of follicular (granulosa) cells • Primary follicles – lifetime supply at birth – remain at this stage until – most never ovulate,but undergo atresia Ovarian Histology

• Secondary follicles – growing follicles – increase in number of layers of granulosa cells – • Tertiary follicles – maturing follicles – antrum formation • fluid filled space – oocyte on mound of granulosa • – granulosa layer immediately around oocyte • Corona radiata – Granulosa surrounded by • • MATURE GRAAFIAN FOLLICLE

Theca cells

Zona Pellucida Oocyte With Nucleus

Corona Radiata Cumulus Oopherus (cumulus granulosa cells) Mural Granulosa Cells Basement Membrane Ovarian Histology • Mature Graafian Follicle – Same structures as tertiary follicle, but larger • Layers of cells & volume of follicular fluid is greater • Stigma-like structure forms on surface of follicle to ovulate • Size of Ovulatory Follicle – Cow • 15-20 mm – Mare • 25-70 mm – Bitch, ewe, doe, sow • 5-10 mm Ovarian Histology • (CH)/Corpora hemorrhagica – newly ruptured follicle – essentially a blood clot • (CL)/Corpora lutea – LH stimulates formation from theca interna and granulosa – temporary endocrine gland • progesterone • (CA)/Corpora albicantia – remains after CL regresses

CORPUS LUTEUM MATURE GRAAFIAN FOLLICLE Follicular Fluid

Theca cells

Zona Pellucida Oocyte With Nucleus

Corona Radiata Cumulus Oopherus (cumulus granulosa cells) Mural Granulosa Cells Basement Membrane

Ovulatory Surge of Luteinizing Hormone

Primates Structural Changes During Luteinization

TC LC A BV O GC Two Cell Theory for Ovarian Sex Steroid Production • THECA CELLS: Cholesterol to Progestins (Pregnenolone and Progesterone and 17-alpha hydroxy progestins) to ( and dehydroepiandrosterone)

• GRANULOSA CELLS: Androgens to VIA AROMATASE ENZYME

• LUTEAL CELLS – Cholesterol to Progesterone Steroidogenesis Before LH Surge

FSH

A

GL Ch P A2 P450scc Arom E2 3b-HSD BM

TI Ch P450scc P A2 E2 17a-HSD 3b-HSD TE

LH A: Antrum; GL: Granulosas; BM; Basement Memb TI: Theca Int. TE: T Ext.; C: Capillaries Ch: Cholesterol; P: Progesterone; A2: Endrogen; E2: Estradiol Luteal Steroidogenesis

Large Luteal Cells

(Some Species) Ch A E P450scc P17 a-HSD 2 Arom 2 3b-HSD

Ch A E P450scc P17 a-HSD 2 Arom 2 3b-HSD Small Luteal Cells

Ch: Cholesterol; P: Progesterone; A2: Endrogen; E2: Estradiol Endocrine Effects of Progesterone

Inhibits LH and FSH Secretion

Lobuloalveolar Contraction Development and Secretion

PROGESTERONE - the HORMONE of ! Differentiation and Secretion

Duration of Luteal Function Across Species

Weeks

Weeks

Days/Weeks

Weeks

Months

Physiological Review 79:263 Tubular Female Reproductive Tract • Oviducts, uterus, cervix, vagina & vestibule • Common basic structure – Four concentric layers • Serosa • Muscularis • Submucosa • Mucosa Female Reproductive Tract

• Suspended in by a fold of peritoneal lining – Broad Ligament: supports vessels, lymphatics & nerves to each part of tract • Mesovarium – Attaches to ovary at hilus • – Supports oviduct • – Supports uterus

Oviduct or

• Supported by mesosalpinx – Open pouch or bursa for ovary; differs among species • Functions – Ovum transport – storage & – Fertilization – • Ciliated epithelial cells – Transport • Nonciliated epithelial cells – Secretory Oviductal Anatomy

• Infundibulum – Funnel-shaped proximal end – Fimbriae – Captures ova • Ampulla – Ovum transport • Ampullary-Isthmic Junction – Site of fertilization • Isthmus – Sperm reservoir – Early embryonic development

Oviductal Secretory Proteins

• Organ specific • Region specific • Cycle specific – Quantitative & qualitative differences • Interaction with – Ova – Embryos – Spermatozoa • Growth factors Tubo-uterine Junction

• Valve-like structure • Regulates passage of – Embryos to uterus – Spermatozoa to oviduct – Other substances: block to entry into the oviduct • Area of accumulation of sperm for movement into the oviduct Uterine Histoarchitecture

R.D. Geisert & L. Burdett

Functions of the Uterus

• Primary functions – Sperm transport to oviducts – Luteolysis & control of cyclicity – Development of the conceptus – Maternal contribution to placenta – Expulsion of fetus and fetal placenta Uterus • Unique nomenclature – Serosa = – Muscularis = – Mucosa + submucosa = • Lumenal Epithelium • Superficial Glandular Epithelium • Glandular Epithelium • Most species have two (cornua) – Classification based on degree of development of uterine body Uterine Classification • Duplex – marsupials, lagomorphs, rodents – 2 cervices, 2 separate horns, no uterine body – Facilitates multi-sire and multi-treatment experiments • Bicornate (cow/ewe/mare)/Bipartite (sow) – Moderate fusion (bipartite) – cow, ewe, doe, mare • 1 cervix, 2 uterine horns, 1 uterine body – Minimal fusion – sow, bitch, queen • 1 cervix, 2 uterine horns, 1short uterine body • Simplex – primates – 1 cervix, no uterine horns, prominent body Uterine Anatomy Subprimate vs Primate Mammals: Distinctions Regarding Tubal Pregnancy and Regulation of Lifespan of the Corpus Luteum (CL) • Primates – Tubal Pregnancy – Uterine Independent Menstrual Cycles

• Subprimates – No Tubal Pregnancy – Uterine Dependent Estrous Cycles Endometrium

• Mucosa + submucosa – Epithelia • Lumenal – Endometrial Glands • Glandular Epithelia • Superficial Glandular Epithelium – Blood vessels – Lymphatics – Stroma • Stratum Compactum • Stratum Spongiosum Life Cycle in Sheep Progestins Inhibit Endometrial Adenogenesis No Glands, No Histotroph, No Pregnancy

Acyclic Infertile Comparative Anatomy • Ruminants – Caruncles • Devoid of glands • Maternal portion of placentome • Vascular sites of attachment to Cotyledons – the vascular fetal portion of placentome • Sow and Mare – Endometrial folds • Primates – Very dynamic – Cyclic sloughing of endometrium (menstruation)

Human Endometrium Human Endometrium

• Secretory Phase – Endometrial thickening • Glands –  secretory activity –  distention –  tortuosity – Stromal edema – Coiled arteries more superficial

Human Endometrium

• Menstrual Phase – Loss of superficial: • Epithelium • Glands • Stroma • Vessels – Necrosis – Deeper structures intact Human Endometrium Uterine Gland Life Cycle in Sheep Uterine Prostaglandins • Produced by endometrium – Arachidonic acid – Specific timing for pulsatile PGF release – estradiol and oxytocin – Uterine irritation/infection • Luteolytic – Vascular spasm – Direct effect on luteal cells • CL sensitivity – Timing • Mare, cow, ewe, doe vs sow – Dose • Sow & ruminants vs mare – Vascular anatomy

The Uterus Regulates the Life Span of the Corpus Luteum.

Hysterectomy

Progesterone Progesterone

1 10 20 1 10 20 Luteal Phase Luteal Phase

Intact Hysterectomized Animal Uterus-Ovary Connection

Ovarian Artery

Ewe Cervix • Separates uterus & vagina • Muscular organ w/constricted lumen – Well developed circular muscle – Many elastic fibers – Highly folded mucosa – Mucous cells in epithelium • Thick tenacious mucus • Cervical plug – Species variation • Anatomy • Physiology • Seals to protect uterus • Ferguson Reflex

Cervix of the Mare

• Dramatic cyclic changes – Length – Diameter – Tone • No mucous glands • Simple muscular ring – Easily dilated Vagina & Vestibule

• Female copulatory organ • Vagina – From cervix to – Fornix • Recess around cervix • Absent in sow and bitch – Mucosa undergoes cyclic changes • Used to stage cycle in bitch • Vestibule – Hymen to vulva – Urethral orifice – Suburethral diverticulum • Cow & sow Vulva & Clitoris • Vulva – • Humans – – – Commissures – Two constrictor muscles • Constrictor vulvae – Striated – posterior • Constrictor vestibuli – Smooth – anterior

• Clitoris – Homologue of penis • Erectile tissue